Non-Hodgkin' s B cell lymphoma (AIDS-lymphoma) is seen in greatly-elevated frequency in HIV-infected people, not only in North America and Europe, but worldwide. In this proposal, studies are presented to elucidate the molecular epidemiology of AIDS-lymphoma. The proposed studies will utilize the resources of the Multicenter AIDS Cohort Study of the Natural History of AIDS (MACS). In prior studies supported by this award, elevated levels of various immune system molecules that are associated with B cell activation, including IL6 and IL10, sCD23, sCD27, sCD44, and IgE, were seen prior to the clinical detection of AIDS-lymphoma. Notably, there were clear differences in the patterns of expression of such B cell-stimulatory molecules seen in different subtypes of AIDS-lymphoma (Burkitt's/SNCCL vs. other subtypes), suggesting that there are differences in the character of the immune dysfunction that precedes the development of different subsets of these cancers. In addition to this, in very recent work we saw that a single-nucleotide polymorphism (SNP) in the IL10 promoter (-592 C/C), which is known to result in increased expression of IL10, was associated with the development of AIDS-lymphoma. These findings are of great significance, since few risk factors have been identified for AIDS-lymphoma. The specific aims of the proposed studies are to determine: I ) if enhanced B cell stimulation, elevated immunoglobulin isotype switch activity, detectable c-myc:Ig gene translocations, and/or detectable circulating B cells with a germinal center-like phenotype, precede the development of AIDS- lymphoma, 2) if SNPs in the genes encoding B cell-stimulatory cytokines (IL6, IL10, TNFalpha, LTalpha, RANTES) are associated with an elevated risk for the development of AIDS-lymphoma, and 3) if subjects who have a genotype that has been seen to be associated with a decreased risk for developing AIDS-lymphoma (CCR5 delta-32 heterozygotes, SDF-1 3'UTR 801 G/G SNP, or IL10 promoter -592 A/A or A/C SNP) show lower levels of B cell activation. The accomplishment of these specific aims will add valuable new information to our understanding of the molecular epidemiology of AIDS-lymphoma, as well as the role of immune dysfunction in the generation and growth of this cancer. This information could form the foundation for future studies on the pathogenesis of AIDS-lymphoma, and may lead to new screening techniques able to detect AIDS-lymphoma earlier in the course of tumor development, allowing for earlier and more effective clinical intervention.